Chronic Lung Disease of Infancy

Pulmonary pericytes are unique cells that offer support to and communicate with angiogenic endothelial cells. Using single cell RNA sequencing (scRNAseq) technique to determine differentially expressed genes in a mouse model of hyperoxia-induced lung injury to mimic bronchopulmonary dysplasia (BPD), pericytes were found to be nearly absent compared to normoxic mice by day 7 of life (P7). The identification of pericyte loss in a BPD mouse model is completely novel and suggests that the angiogenic deficiency found in patients with BPD may be pericyte dependent.

We have developed a novel protocol to isolate pericytes from various stages of pulmonary development. Preliminary results have shown that Hypoxia Inducible Factor (HIF) signaling may play a role in the early stages of hyperoxia-induced lung injury. Future studies will explore the role of pericytes in endothelial cell-driven pulmonary angiogenesis.

In lung development, the most important process in alveolarization is when the alveolar ducts divide into alveolar sacs by secondary septation. We now know that angiogenesis drives this process. HIF-1a is a transcription factor important for angiogenesis, especially under conditions in which oxygen levels are limited. Infants born prematurely (less than 28 weeks gestational age) and treated with supplemental oxygen exhibit arrested lung development with impaired alveolarization and loss of angiogenesis, resulting in Bronchopulmonary Dysplasia (BPD).

The role of HIF-1a in the development of BPD remains unknown; therefore, to clarify the effects of HIF-1a, we created mice with a cell-specific deletion of HIF-1a. Mice with a SM22a cell-specific deletion of HIF-1a show impaired pulmonary development consistent with BPD. The loss of HIF-1a resulted in a loss of Angiopoietin 2, a secreted molecule essential for angiogenesis, suggesting that the loss of Angiopoietin 2 may be a factor in the development of BPD.

Though the survival rates for preterm infants are improving, the incidence of chronic lung disease of infancy, or Bronchopulmonary Dysplasia (BPD), remains high. BPD is characterized by larger and fewer alveoli (air sacs). We have previously shown that the loss of HIF-1α expression in a mouse model of BPD impairs alveolarization and angiogenesis. Therefore, we sought to determine if HIF-1α stabilization in SM22α-expressing cells can limit hyperoxia-induced neonatal lung injury, a mouse model of BPD. In mice expressing stabilized HIF-1a, (SM22α-PHD1/2^-/- mice) we found that stabilization of HIF-1α in pulmonary SM22α-expressing cells protects neonatal lung development despite prolonged hyperoxia exposure. In addition, Angiopoietin 2, microvascularization, and angiogenesis were increased in mice expressing stabilized HIF-1α.

In Bronchopulmonary Dysplasia (BPD), lung function continues to deteriorate until adulthood leading to obstructive pulmonary disease. Moreover, ~20% of BPD patients suffer from Pulmonary Hypertension (PH), and in BPD patients diagnosed with PH there is a higher mortality rate (~50%).

In our SM22a-PHD1/2 BPD mouse model we have found that not only are SM22a-PHD1/2^-/- mice protected from developing BPD, but as adults are protected from developing PH. These mice exhibit diminished pulmonary arterial wall thickness and right ventricular hypertrophy compared to control mice. 

Bronchopulmonary dysplasia (BPD) affects infants born prematurely due to the lack of mature lung function. HIF-1a has been found to be an invaluable component in the maturing lung; therefore, we made a mouse lacking SMC-HIF-1a and found that these mice maintain an immature lung phenotype, resembling the human condition.